During mammalian retinal development a complex sequence of molecular events leads to the precise laminations and interconnections of the mature retina. In normal mature human retinas, rod and cone photoreceptors start the processing of vision, which proceeds through bipolar and ganglion cell retinal pathways to the brain [1]. Hereditary disease can perturb these retinal pathways and cause either progressive degeneration or more stationary visual deficits [2]. Congenital stationary night blindness (CSNB) is a group of retinopathies that fall into the latter category of a selective retinal pathway disturbance that manifest at birth. CSNB has been recognized clinically for more than 100 years; genetic subtypes have been defined; and different sites of disease action have been postulated [3-5].
Patients with X-linked CSNB phenotypically exhibit normal fundi, but generally have reduced visual acuity, impaired night vision and, in addition, may exhibit myopia (or occasionally hyperopia), and nystagmus. Based on electroretinographic findings, patients with X-linked CSNB can have one of two forms of X-linked CSNB—complete or incomplete [4,6]. This clinical heterogeneity correlates with underlying genetic heterogeneity in which complete X-linked CSNB segregates with the CSNB1 locus in Xp11.4, and incomplete X-linked CSNB segregates with the CSNB2 locus in Xp11.23 [6,7]. Patients with incomplete X-linked CSNB who show both impaired rod and cone function were recently shown to have mutations in a voltage-gated L-type calcium channel α-1F-subunit gene, CACNA1F [8,9]. The electroretinographic findings in patients with complete X-linked CSNB indicates a specific defect in the ON pathway of the retina, namely the retinal circuitry which transmits the visual signal from the majority if not all of the rod photoreceptor cells and a subset of the cone photoreceptors. This signal is mediated via the rod and cone on-bipolar retinal neurons.
The biochemical defects underlying complete X-linked CSNB is unknown but may be revealed by identifying the gene, CSNB1, involved in this disorder. The CSNB1 locus was reported to be on the proximal portion of the human X chromosome, between DXS556 and DXS8083, as described previously [6].
The identification of the gene which is causative of complete X-linked CSNB may allow for development of diagnostic tests for this disorder and risk assessment in members of affected families. As well, identification of the gene that is causative of complete X-linked CSNB will provide information as to the basic defect in this retinal condition, which could lead to effective methods for treatment or cure of the disorder. In as much as the identification of the gene for complete X-linked CSNB and its encoded protein will provide understanding of the general mechanism of neurotransmission and the development of neuronal circuitry [1], this discovery may have implications for understanding the formation of neural circuits in general.
Leucine-rich repeat glycoproteins form part of the extracellular matrix (ECM) of mammalian cells [10]. The major components of the ECM are collagens, proteoglycans, glycosaminoglycans, fibronectin and, to a lesser extent, glycoproteins. These components are organized into a fibrillar meshwork, to provide mechanical strength and elasticity, and to create a structural framework that provides a substratum for cell adhesion and migration. The ECM plays an integral role in the pivotal processes of development, tissue repair, and metastasis. Within the ECM, the leucine-rich repeat glycoproteins are likely to perform more than a structural role, and also likely to be involved in regulating cell growth, adhesion and migration.
Many cell-surface proteins are anchored to the external surface of the plasma membrane by covalently attached glycosyl-inositol phospholipids (“GPIs”). These anchors use a common structure as a general mechanism for membrane attachment, irrespective of protein function, and are added post-translationally at the time of the translocation of the protein across the endoplasmic reticulum [11].
The N-terminus of a secreted protein usually consists of a cleavable leader of 15-30 amino acids, which is called a signal sequence. The signal sequence is both necessary and sufficient for transfer of any attached polypeptide to the target membrane and is responsible for directing ribosomes to attach to the endoplasmic reticulum as soon as the first few N-terminal amino acids are synthesized [12].
The identification of the gene, mutations of which cause complete X-linked CSNB, will aid in the elucidation of the role of the protein in retinal function, and neurotransmission. Knowledge of the structure of this gene, from both naturally occurring mutations and engineered variants of the protein, will lead to studies of the structure-function relationships of the protein in the cellular environment and its role in the disease process. Further, the identification of the gene will provide a tool for the diagnosis of complete X-linked CSNB in individuals suspected of having this disorder.